Submissions for variant NM_000251.3(MSH2):c.2362dup (p.Thr788fs)

dbSNP: rs63750463

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076464	SCV000107493	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Coding sequence variation introducing premature termination codon
GeneDx	RCV000480512	SCV000568636	pathogenic	not provided	2015-12-02	criteria provided, single submitter	clinical testing	This duplication of one nucleotide in MSH2 is denoted c.2362dupA at the cDNA level and p.Thr788AsnfsX11(T788NfsX11) at the protein level. The normal sequence, with the base that is duplicated in braces, is ACTT[A]CTGC. The duplication causes a frameshift, which changes a Threonine to an Asparagine at codon 788, and creates a premature stop codon at position 11 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.2362dupA has been identified in at least one individual meeting Amsterdam II criteria whose colon tumor showed absence of MSH2 protein by immunohistochemistry (Pedroni 2007). We consider this variant to be pathogenic.
Ambry Genetics	RCV000490851	SCV000580625	pathogenic	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	The c.2362dupA pathogenic mutation, located in coding exon 14 of the MSH2 gene, results from a duplication of A at nucleotide position 2362, causing a translational frameshift with a predicted alternate stop codon (p.T788Nfs*11). This alteration has been reported in an Italian individual whose family history met Amsterdam II criteria and whose colon tumor was MSI-H and showed absence of the MSH2 protein on immunohistochemistry analysis (Pedroni M et al. Dis. Markers 2007; 23(3):179-87). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV001040813	SCV001204403	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-05-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 90962). This premature translational stop signal has been observed in individual(s) with an MSH2-related cancer (PMID: 17473388, 29348823). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr788Asnfs*11) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816).
Myriad Genetics, Inc.	RCV003452908	SCV004188055	pathogenic	Lynch syndrome 1	2023-08-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.